scholarly journals Protein products of non-stop mRNA disrupt nucleolar homeostasis

2019 ◽  
Author(s):  
Zoe H. Davis ◽  
Laura Mediani ◽  
Jonathan Vinet ◽  
Simon Alberti ◽  
Alex S. Holehouse ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disease ◽  
Molecular Interactions ◽  
Protective Response ◽  
Cellular Processes ◽  
Ribosome Stalling ◽  
Stress Changes ◽  
Simple Physical Model ◽  
Resistance To Stress ◽  
Nucleolar Components

SummaryMutations that cause ribosome stalling or impair the cell’s protective response to stalling have been demonstrated to cause neurodegeneration, yet the mechanisms underlying these pathologies remain poorly understood. Here we investigated the fate of defective proteins translated from stall-inducing, nonstop mRNA that escape ubiquitylation by the Ribosome-associated Quality Control (RQC) E3 ligase LTN1. We found that nonstop protein products accumulated in nucleoli and this localization was driven by polylysine tracts produced by translation of the poly(A) tail of nonstop mRNA. Nucleolar sequestration increased the solubility of invading proteins but disrupted nucleoli, altering their dynamics, morphology, and resistance to stress. Changes in nucleolar morphology are consistent with a simple physical model in which LTN1 impairment enhances the inter-molecular interactions of nucleolar components. Our work elucidates how failure to degrade the protein products of stalled translation may affect distal cellular processes and will inform studies on the pathology of neurodegenerative disease.

scholarly journals NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Paige B. Martin ◽  
Yu Kigoshi-Tansho ◽  
Roger B. Sher ◽  
Gianina Ravenscroft ◽  
Jennifer E. Stauffer ◽  
...  
Keyword(s):  
Quality Control ◽  
Nervous System ◽  
Mouse Models ◽  
Human Disease ◽  
Neuromuscular Disease ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Ribosome Stalling

Abstract A hallmark of neurodegeneration is defective protein quality control. The E3 ligase Listerin (LTN1/Ltn1) acts in a specialized protein quality control pathway—Ribosome-associated Quality Control (RQC)—by mediating proteolytic targeting of incomplete polypeptides produced by ribosome stalling, and Ltn1 mutation leads to neurodegeneration in mice. Whether neurodegeneration results from defective RQC and whether defective RQC contributes to human disease have remained unknown. Here we show that three independently-generated mouse models with mutations in a different component of the RQC complex, NEMF/Rqc2, develop progressive motor neuron degeneration. Equivalent mutations in yeast Rqc2 selectively interfere with its ability to modify aberrant translation products with C-terminal tails which assist with RQC-mediated protein degradation, suggesting a pathomechanism. Finally, we identify NEMF mutations expected to interfere with function in patients from seven families presenting juvenile neuromuscular disease. These uncover NEMF’s role in translational homeostasis in the nervous system and implicate RQC dysfunction in causing neurodegeneration.

scholarly journals Role for ribosome-associated quality control in sampling proteins for MHC class I-mediated antigen presentation

2020 ◽  
Vol 117 (8) ◽  
pp. 4099-4108 ◽  
Author(s):  
Débora Broch Trentini ◽  
Matteo Pecoraro ◽  
Shivani Tiwary ◽  
Jürgen Cox ◽  
Matthias Mann ◽  
...  
Keyword(s):  
Quality Control ◽  
Antigen Presentation ◽  
Mammalian Cells ◽  
Adaptive Immune System ◽  
Messenger Rnas ◽  
Mhc I ◽  
Adaptive Immune ◽  
Ribosome Stalling ◽  
Endogenous Substrates ◽  
Insight Into

Mammalian cells present a fingerprint of their proteome to the adaptive immune system through the display of endogenous peptides on MHC-I complexes. MHC-I−bound peptides originate from protein degradation by the proteasome, suggesting that stably folded, long-lived proteins could evade monitoring. Here, we investigate the role in antigen presentation of the ribosome-associated quality control (RQC) pathway for the degradation of nascent polypeptides that are encoded by defective messenger RNAs and undergo stalling at the ribosome during translation. We find that degradation of model proteins by RQC results in efficient MHC-I presentation, independent of their intrinsic folding properties. Quantitative profiling of MHC-I peptides in wild-type and RQC-deficient cells by mass spectrometry showed that RQC substantially contributes to the composition of the immunopeptidome. Our results also identify endogenous substrates of the RQC pathway in human cells and provide insight into common principles causing ribosome stalling under physiological conditions.

Protein Quality Control Degradation in the Nucleus

2018 ◽  
Vol 87 (1) ◽  
pp. 725-749 ◽  
Author(s):  
Charisma Enam ◽  
Yifat Geffen ◽  
Tommer Ravid ◽  
Richard G. Gardner
Keyword(s):  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Current Knowledge ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Cellular Processes ◽  
Human Disorders ◽  
Protein Misfolding And Aggregation

Nuclear proteins participate in diverse cellular processes, many of which are essential for cell survival and viability. To maintain optimal nuclear physiology, the cell employs the ubiquitin-proteasome system to eliminate damaged and misfolded proteins in the nucleus that could otherwise harm the cell. In this review, we highlight the current knowledge about the major ubiquitin-protein ligases involved in protein quality control degradation (PQCD) in the nucleus and how they orchestrate their functions to eliminate misfolded proteins in different nuclear subcompartments. Many human disorders are causally linked to protein misfolding in the nucleus, hence we discuss major concepts that still need to be clarified to better understand the basis of the nuclear misfolded proteins’ toxic effects. Additionally, we touch upon potential strategies for manipulating nuclear PQCD pathways to ameliorate diseases associated with protein misfolding and aggregation in the nucleus.

scholarly journals Widespread ribosome stalling in a genome-reduced bacterium and the need for translational quality control

iScience ◽  
2021 ◽  
pp. 102985
Author(s):  
Raul Burgos ◽  
Marc Weber ◽  
Carolina Gallo ◽  
Maria Lluch-Senar ◽  
Luis Serrano
Keyword(s):  
Quality Control ◽  
Ribosome Stalling ◽  
A Genome

scholarly journals From cartoons to quantitative models in Golgi transport

2020 ◽  
Author(s):  
D. Nicolas Quiros ◽  
Luis S. Mayorga
Keyword(s):  
Golgi Apparatus ◽  
Mathematical Models ◽  
Chemical Reactions ◽  
Molecular Interactions ◽  
Cell Biology ◽  
Lipid Transport ◽  
Self Organization ◽  
Agent Based ◽  
Cellular Processes ◽  
Golgi Transport

ABSTRACTCell biology is evolving to become a more formal and quantitative science. In particular, several mathematical models have been proposed to address Golgi self-organization and protein and lipid transport. However, most scientific articles about the Golgi apparatus are still using static cartoons to represent their findings that miss the dynamism of this organelle. In this report, we show that schematic drawings of Golgi trafficking can be easily translated into an Agent-Based Model (ABM) using the Repast platform. The simulations generate an active interplay among cisternae and vesicles rendering quantitative predictions about Golgi stability and transport of soluble and membrane-associated cargoes. The models can incorporate complex networks of molecular interactions and chemical reactions by association with COPASI, a software that handles Ordinary Differential Equations. The strategy described provides a simple, flexible, and multiscale support to analyze Golgi transport. The simulations can be used to address issues directly linked to the mechanism of transport or as a way to incorporate the complexity of trafficking to other cellular processes that occur in dynamic organelles.

scholarly journals Quality Matters? The Involvement of Mitochondrial Quality Control in Cardiovascular Disease

2021 ◽  
Vol 9 ◽  
Author(s):  
Kai-Lieh Lin ◽  
Shang-Der Chen ◽  
Kai-Jung Lin ◽  
Chia-Wei Liou ◽  
Yao-Chung Chuang ◽  
...  
Keyword(s):  
Quality Control ◽  
Cardiovascular Diseases ◽  
Power Plants ◽  
Mitochondrial Dynamics ◽  
Ischemia Reperfusion ◽  
Cardiovascular Complications ◽  
Cellular Survival ◽  
Cellular Processes ◽  
High Workload ◽  
Continuous Power

Cardiovascular diseases are one of the leading causes of death and global health problems worldwide. Multiple factors are known to affect the cardiovascular system from lifestyles, genes, underlying comorbidities, and age. Requiring high workload, metabolism of the heart is largely dependent on continuous power supply via mitochondria through effective oxidative respiration. Mitochondria not only serve as cellular power plants, but are also involved in many critical cellular processes, including the generation of intracellular reactive oxygen species (ROS) and regulating cellular survival. To cope with environmental stress, mitochondrial function has been suggested to be essential during bioenergetics adaptation resulting in cardiac pathological remodeling. Thus, mitochondrial dysfunction has been advocated in various aspects of cardiovascular pathology including the response to ischemia/reperfusion (I/R) injury, hypertension (HTN), and cardiovascular complications related to type 2 diabetes mellitus (DM). Therefore, mitochondrial homeostasis through mitochondrial dynamics and quality control is pivotal in the maintenance of cardiac health. Impairment of the segregation of damaged components and degradation of unhealthy mitochondria through autophagic mechanisms may play a crucial role in the pathogenesis of various cardiac disorders. This article provides in-depth understanding of the current literature regarding mitochondrial remodeling and dynamics in cardiovascular diseases.

scholarly journals Polyamines as Quality Control Metabolites Operating at the Post-Transcriptional Level

Plants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Laetitia Poidevin ◽  
Dilek Unal ◽  
Borja Belda-Palazón ◽  
Alejandro Ferrando
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Physiological Functions ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Ribosome Stalling ◽  
Molecular Functions

Plant polyamines (PAs) have been assigned a large number of physiological functions with unknown molecular mechanisms in many cases. Among the most abundant and studied polyamines, two of them, namely spermidine (Spd) and thermospermine (Tspm), share some molecular functions related to quality control pathways for tightly regulated mRNAs at the level of translation. In this review, we focus on the roles of Tspm and Spd to facilitate the translation of mRNAs containing upstream ORFs (uORFs), premature stop codons, and ribosome stalling sequences that may block translation, thus preventing their degradation by quality control mechanisms such as the nonsense-mediated decay pathway and possible interactions with other mRNA quality surveillance pathways.

scholarly journals MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases

2020 ◽  
Vol 2 (3) ◽  
pp. 282-307
Author(s):  
Chisato Kinoshita ◽  
Yayoi Okamoto ◽  
Koji Aoyama ◽  
Toshio Nakaki
Keyword(s):  
Circadian Rhythm ◽  
Circadian Rhythms ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Sleep Disorders ◽  
Physiological Activity ◽  
Post Translational Modification ◽  
Cellular Processes ◽  
Non Coding Rna ◽  
And Behavior

Circadian rhythms are endogenous 24-h oscillators that regulate the sleep/wake cycles and the timing of biological systems to optimize physiology and behavior for the environmental day/night cycles. The systems are basically generated by transcription–translation feedback loops combined with post-transcriptional and post-translational modification. Recently, evidence is emerging that additional non-coding RNA-based mechanisms are also required to maintain proper clock function. MicroRNA is an especially important factor that plays critical roles in regulating circadian rhythm as well as many other physiological functions. Circadian misalignment not only disturbs the sleep/wake cycle and rhythmic physiological activity but also contributes to the development of various diseases, such as sleep disorders and neurodegenerative diseases. The patient with neurodegenerative diseases often experiences profound disruptions in their circadian rhythms and/or sleep/wake cycles. In addition, a growing body of recent evidence implicates sleep disorders as an early symptom of neurodegenerative diseases, and also suggests that abnormalities in the circadian system lead to the onset and expression of neurodegenerative diseases. The genetic mutations which cause the pathogenesis of familial neurodegenerative diseases have been well studied; however, with the exception of Huntington’s disease, the majority of neurodegenerative diseases are sporadic. Interestingly, the dysfunction of microRNA is increasingly recognized as a cause of sporadic neurodegenerative diseases through the deregulated genes related to the pathogenesis of neurodegenerative disease, some of which are the causative genes of familial neurodegenerative diseases. Here we review the interplay of circadian rhythm disruption, sleep disorders and neurodegenerative disease, and its relation to microRNA, a key regulator of cellular processes.

scholarly journals Cell viability and secretion of active proteins in Schizosaccharomyces pombe do not require the chaperone function of calnexin

2004 ◽  
Vol 380 (2) ◽  
pp. 441-448 ◽  
Author(s):  
Alexandre MARÉCHAL ◽  
Pierre-Luc TANGUAY ◽  
Mario CALLEJO ◽  
Renée GUÉRIN ◽  
Guy BOILEAU ◽  
...  
Keyword(s):  
Quality Control ◽  
Schizosaccharomyces Pombe ◽  
Secretory Pathway ◽  
Cellular Processes ◽  
Rate Limiting Step ◽  
Secretion Efficiency ◽  
Model Protein ◽  
Endogenous Proteins ◽  
Quality Control Mechanism

Folding of newly synthesized proteins within the ER (endoplasmic reticulum) is a rate-limiting step in protein secretion. Thus ER molecular chaperones and foldases have a major impact in determining the rate and yield of these crucial cellular processes. Calnexin is a key ER chaperone implicated in the folding, retention and targeting for degradation of proteins that go through the secretory pathway. Calnexin molecules contain a highly conserved central domain (hcd) that has been proposed to be involved in the interaction with folding substrates and other chaperones. To gain a better understanding of the roles played by calnexin in the secretory pathway, we examined the efficiency of fission yeast (Schizosaccharomyces pombe) strains expressing calnexin mutants to secrete different model proteins. Remarkably, calnexin hcd-deletion mutants, although devoid of detectable chaperone activity in vitro, confer viability and cause a considerable increase in the secretion of heterologous cellulase. Surprisingly the quality-control efficiency, measured as the activity/amount ratio of secreted model protein, was not severely reduced in these calnexin hcd-deletion mutant strains. Our results indicate that the essential function of calnexin does not reside in its role in the folding or in the retention of misfolded proteins. These observations suggest the existence of a highly stringent quality control mechanism in the ER of S. pombe that might reduce the secretion efficiency of endogenous proteins.

scholarly journals Motility Plays an Important Role in the Lifetime of Mammalian Lipid Droplets

2021 ◽  
Vol 22 (8) ◽  
pp. 3802
Author(s):  
Yi Jin ◽  
Zhuqing Ren ◽  
Yanjie Tan ◽  
Pengxiang Zhao ◽  
Jian Wu
Keyword(s):  
Signal Transduction ◽  
Endoplasmic Reticulum ◽  
Lipid Droplet ◽  
Molecular Basis ◽  
Lipid Droplets ◽  
Neutral Lipids ◽  
Future Research ◽  
Biological Processes ◽  
Cellular Processes ◽  
Resistance To Stress

The lipid droplet is a kind of organelle that stores neutral lipids in cells. Recent studies have found that in addition to energy storage, lipid droplets also play an important role in biological processes such as resistance to stress, immunity, cell proliferation, apoptosis, and signal transduction. Lipid droplets are formed at the endoplasmic reticulum, and mature lipid droplets participate in various cellular processes. Lipid droplets are decomposed by lipase and lysosomes. In the life of a lipid droplet, the most important thing is to interact with other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and autophagic lysosomes. The interaction between lipid droplets and other organelles requires them to be close to each other, which inevitably involves the motility of lipid droplets. In fact, through many microscopic observation techniques, researchers have discovered that lipid droplets are highly dynamic organelles that move quickly. This paper reviews the process of lipid droplet motility, focusing on explaining the molecular basis of lipid droplet motility, the factors that regulate lipid droplet motility, and the influence of motility on the formation and decomposition of lipid droplets. In addition, this paper also proposes several unresolved problems for lipid droplet motility. Finally, this paper makes predictions about the future research of lipid droplet motility.

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